Quiescence in cell cycle, a characteristic distinguishing a hematopoietic stem cell from a progenitor cell, has been shown to be a necessary protective feature for maintaining the stemness in vivo but a barrier for therapeutic manipulation in vitro. Current efforts intended to breaking the stem cell quiescence have been focused on cytokine-driven ex vivo expansion, but have had limited success because of the loss of multi-potentiality and the inefficient gene transduction after ex vivo manipulation. Less attention has been paid on the efficiency of stem cell repopulation in vivo. We have found that the proliferation of stem cells or progenitor cell s regulated by different cyclin-dependent kinase inhibitors (CDKIs) and stem cell characteristic can be well maintained in the absence of a progenitor cell specific CDKI, p27. We hypothesize that an enhanced hematopoietic repopulation can be achieved without necessarily increasing stem cells number by targeting the progenitor specific CDKIs. Therefore, this project is intended to focus on: 1) Determine if stem cell down-stream progeny is specifically expanded in the absence of a new member of CDKI, pl8 or both p18 and p27 using the knockout mice as models by the in vitro and in vivo stem/progenitor assays. 2) Determine if the long-term repopulation efficiency is increased without apparent leukemia in the absence of p18 or/and p 27 in a competitively repopulating transplant model. 3) Determine if human long-term hematopoietic repopulation or gene transduction can enhanced by targeting p27 or pl8 as assessed by an immuno-deficient mouse model. The central hypothesis to be tested is that targeting progenitor-specific CDKIs at stem cell level is able to enhance stem cell efficiency without necessarily affecting stem cell cycling or number.